1. Field of the Invention
This invention relates generally to expandable intraluminal vascular grafts and stents, and more particularly concerns grafts and stents coated or covered with an open-celled microcellular polymeric foam component capable of carrying and releasing therapeutic drugs, and a method of incorporating therapeutic drugs into the open-celled microcellular polymeric foam component of such grafts and stents.
2. Description of Related Art
Vascular grafts and stents are vascular interventional devices that are typically implanted within a vessel in a contracted state and expanded when in place in the vessel in order to maintain patency of the vessel to allow fluid flow through the vessel. Ideally, implantation of such vascular interventional devices is accomplished by moving the device along a guide wire previously placed in the vessel, and expanding and locking the device in an expanded state by inflation of a balloon within the device. The graft or stent can then be left in place by deflating the balloon and removing the guide wire. However, restenosis of blood vessels, such as coronary vessels treated with percutaneous transluminal coronary angioplasty (PTCA) or stents is a current clinical challenge. To address this problem, various approaches are being developed to reduce restenosis by locally delivering drugs to the target site of possible restenosis.
Stents commonly have a metallic structure to provide the strength required to function as a stent, but commonly have been unable to satisfactorily deliver localized therapeutic pharmacological agents to a blood vessel at the location being treated with the stent. While polymeric materials that can be loaded with and release drugs or other pharmacological treatments can be used for drug delivery, polymeric materials may not fulfill the structural and mechanical requirements of a stent, especially when the polymeric materials are loaded with a drug, since drug loading of a polymeric material can significantly affect the structural and mechanical properties of the polymeric material. Since it is often useful to provide localized therapeutic pharmacological treatment of a blood vessel at the location being treated with the stent, it would be desirable to provide a polymeric component for grafts and stents to provide the capability of being loaded with therapeutic drugs, to function together with the graft or stent for placement and release of the therapeutic drugs at a specific intravascular site.
Commonly used grafts in the industry are formed from expanded polytetrafluoroethylene (ePTFE), and knitted polyesters such as Dacron. However, the use of grafts formed with such polymeric material is typically restricted to larger vessels greater than about four millimeters in diameter. When used with narrower blood vessels, these types of grafts tend to become occluded. Moreover, the compliance of such grafts commonly does not match that of natural artery. In recent years, improved polymers such as polyurethanes containing carbonate linkages, such as that available under the trade name xe2x80x9cCARBOTHANExe2x80x9d from The Carboline Company of St. Louis, Mo., and the material available under the trade name xe2x80x9cCHRONOFLEXxe2x80x9d from CardioTech International, Inc. of Woburn, Mass., have been developed for use in forming small bore vascular grafts. The mechanical characteristics of these grafts are close to that of natural arteries.
Such a polymeric component for use in forming vascular grafts and stent covers capable of carrying and delivering therapeutic drugs should have a microporous, open-celled structure, because the porosity not only allows the material to carry and deliver therapeutic drugs, but also permits ingrowth into the material of cells and capillaries that take part in the healing process, and can nurture the pseudointima. Currently, process techniques that have commonly been employed to make these polymers microporous include laser drilling of holes in the polymer tubing, and extrusion of the polymeric material with blowing agents, which may be chemicals or gas, to create cells in the extruded tubing. Laser drilling of such material produces holes in the material, while extrusion with blowing agents commonly results in large non-uniform cells on the order of millimeters in diameter. However, conventional foaming techniques that use blowing agents, either using chemical blowing agents or gas assisted blowing agents, do not typically result in an open-celled reticulated structure with an accurately controlled, uniform cell size.
Microcellular polymeric foams are also known that are characterized by cell sizes in the range of 0.1 to 100 microns, with cell densities in the range of 109 to 1015 cells per cubic cm. Typically, such microcellular polymeric foams exhibit properties comparable or superior to properties of structural foams, and, in some cases to the unfoamed polymer. Suitable microcellular foams are currently preferably produced by exposure of the thermoplastic polymer to super-critical CO2 fluid under high temperature and pressure to saturate the thermoplastic polymer with the super-critical CO2 fluid, and then cooling the thermoplastic polymer to foam the amorphous and semi-crystalline thermoplastic polymers. Such suitable microcellular foams can be produced as described in U.S. Pat. Nos. 4,473,665 and 5,160,674, incorporated herein by reference in their entirety. The foaming process can be carried out on extruded polymer tubing of the proper dimension. The first stage of microcellular foam processing involves dissolving an inert gas, such as nitrogen or CO2, under pressure into the polymer matrix. The next phase is the rapid creation of microvoids. This is initiated by inducing large thermodynamic instability. The thermodynamic instability is induced by quickly decreasing the solubility of the gas in the polymer by changing the pressure or temperature.
There remains a need for vascular grafts and stent covers having a porosity that can be controlled to be suitable for the types of therapeutic drugs to be carried and delivered to a target site to be treated. The present invention meets this and other needs.
Briefly, and in general terms, the present invention provides for improved porous vascular grafts and stent covers formed of open-celled microcellular polymeric foams having a porosity that can be modified to be adapted for carrying and delivering different types of therapeutic drugs. The morphology of the open-celled microcellular polymeric foams, including the openness, cell size and porosity of the foams, can be controlled so that the cell sizes can be made very uniform, and can be controlled precisely by changing thermodynamic variables like pressure and temperature during formation of the open-celled microcellular polymeric foams. The open-celled microcellular polymeric foams can be formed by a batch process that can be easily controlled and operated, in which extruded tubing can be cut to the desired lengths and then foamed in separate pressure chamber.
The invention accordingly provides for a stent cover that can be used to carry and deliver therapeutic drugs or as an overcoat barrier layer to control drug release by a drug-coated stent. In one presently preferred embodiment, such a stent cover comprises a tubular member for use with a stent, the stent cover including at least one layer of a porous, microcellular foam formed from a polymeric material capable of absorbing and releasing therapeutic drugs at predictable rates for delivery of the therapeutic drugs in localized drug therapy in a blood vessel. The layer of porous, microcellular foam can range in thickness from about a few nanometers to a millimeter, and the diameter of the pores and the amount of porosity in the foam can be adjusted according to the molecular weight of the drug compound. The diameter of the pores or cells of the microcellular foam can, for example, be made as small as about a few nanometers to accommodate low molecular weight compounds with molecular weights in the range of 10-1,000 daltons up to large molecular weight compounds with molecular weight in the range of 1,000 to 100,000 daltons, as well as supra molecular structures with molecular weights greater than 100,000 daltons. The polymeric material from which the microcellular foam can be formed include polyurethanes containing carbonate linkages, and biodegradable polymers such as poly-L-lactic acid (PLLA), poly-DL-lactic acid (DL-PLA), polyglycolic acid (PGA), p-dioxanone, and trimethylene carbonate/glycolic acid copolymers (TMC/PGA), for example, although other similar materials may also be suitable. Examples of supra molecular structures include viral particles used for gene therapy, liposomes, ribozymes, and the like.
In another aspect, the invention also provides for a composite metal and polymer vascular graft or coated stent, comprising an interior structural stent member, and an outer layer or coating of a porous, microcellular foam formed from a polymeric material capable of absorbing and releasing therapeutic drugs at predictable rates for delivery of the therapeutic drugs in localized drug therapy in a blood vessel. In a currently preferred embodiment, the stent can be formed of a metal such as stainless steel, tantalum, a composite of tantalum and silicon carbide, gold, or can be formed of a polymer, or of a composite. Other metals that may also be suitable for forming the stent include nickel-titanium alloy, platinum-iridium alloy, molybdenum-rhenium alloy, gold, magnesium, and combinations thereof. The porous, microcellular foam can range in thickness from about a few nanometers to a millimeter, and the diameter of the pores and the amount of porosity in the foam can be adjusted according to the molecular weight of the drug compound. The diameter of the pores or cells of the microcellular foam can, for example, be made as small as about a few nanometers to accommodate low molecular weight compounds with molecular weights in the range of 10-1,000 daltons up to large molecular weight compounds with molecular weight in the range of 1,000 to 100,000 daltons and supramolecular structures with molecular weights greater than 100,000 daltons. The polymeric material from which the microcellular foam can be formed include polyurethanes containing carbonate linkages, and biodegradable polymers such as poly-L-lactic acid (PLLA), poly-DL-lactic acid (DL-PLA), polyglycolic acid (PGA), p-dioxanone, and trimethylene carbonate/glycolic acid copolymers (TMC/PGA), for example, although other similar materials may also be suitable. Examples of supra molecular structures include viral particles used for gene therapy, liposomes, ribozymes, and the like.
In another aspect, the present invention also provides for a method of making a composite metal and polymer vascular graft or coated stent, including an interior structural stent member and an outer layer or coating of a porous, microcellular foam formed from a polymeric material capable of absorbing and releasing therapeutic drugs at predictable rates for delivery of the therapeutic drugs in localized drug therapy in a blood vessel, comprising the steps of providing a stent, and coating the stent with an outer layer or coating of a porous, microcellular foam formed from a polymeric material capable of absorbing and releasing therapeutic drugs at predictable rates for delivery of the therapeutic drugs in localized drug therapy in a blood vessel. In another aspect, the method can further comprise the step of loading a therapeutic drug into the outer layer or coating of a porous, microcellular foam for delivery of the therapeutic drugs in localized drug therapy in a blood vessel. The porous, microcellular foam can be formed with different thicknesses, pore sizes, pore distributions, and pore-size gradients to control drug release or pharmacokinetics, as desired.
Preferred examples of therapeutic drugs or pharmacologic compounds that may be loaded into the outer layer of the composite metal and polymer vascular graft or coated stent or into the stent cover and delivered to the target site in the vasculature, or loaded onto the stent over which the stent cover is to be disposed for controlling the drug release of the drug coated stent include taxol, aspirin, prostaglandins, and the like. Therapeutic agents that may also be suitable for loading into the stent cover or for moderation of drug release from the covered stent may also include, for example, antiplatelets, antithrombins, cytostatic or antiproliferative agents, sodium heparin, low molecular weight heparin, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein IIb/IIIa platelet membrane receptor antibody, recombinant hirudin, thrombin inhibitor, angiopeptin, angiotensin converting enzyme inhibitors, Lisinopril, and cisplatin; anti-inflammatories such as steroids; anti-cancer compounds such as taxon and actinomycin; macromolecules such as peptides, proteins, genes and antisense compounds; calcium channel blockers, colchicine, fibroblast growth factor antagonists, fish oil, omega 3-fatty acid, histamine antagonists, HMG-CoA reductase inhibitor, methotrexate, monoclonal antibodies, nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitor, serotonin blockers, thioprotease inhibitors, triazolopyrimidine and other PDGF antagonists, alpha-interferon and genetically engineered epithelial cells, supramolecular weight structures with molecular weights greater than 100,000 daltons, and up to about 1,000,000 daltons, including viral particles used for gene therapy, ribozymes and liposomes, and combinations thereof.